dangerous imitator. immune cells primed to identify invading viruses or bacteria may attack the body's own cells as foreign antigen ( left ) mimics an antigen "auto" ( right ).
Adapted from Dimitry Schidlovsky by G. Grullón / Science
The swine flu pandemic of late 09 had a particular impact in parts of Europe: a peak in children being diagnosed with narcolepsy, a sleep disorder incurable with symptoms including episodes of overwhelming daytime sleepiness. Researchers eventually linked a vaccine widely used to ward off the flu virus H1N1 in a small but increased risk of narcolepsy in children and adolescents. The vaccine, Pandemrix, used only in Europe, apparently triggered disorder in recipients about one in 16,000 in Finland. Sweden, Ireland and England have also found an increased risk, but not as dramatic as Finland.
Now, scientists have a clue of why that points to a new understanding of narcolepsy itself, they report this week Science Translational Medicine . They found that patients with the disease have immune cells that are pushed to the attack by hypocretin, a hormone that regulates wakefulness. Scientists knew that the neurons that produce hypocretin are missing in the narcoleptic brain, but why they go is a mystery. The work reveals "fingerprints of an immune attack," said Lawrence Steinman neuroimmunologist Stanford University in Palo Alto, California, who was not involved in the research. It suggests that autoimmune reaction perhaps triggered by Pandemrix may underlie cases related vaccines. researchers also believe that the flu itself could trigger other cases.
When the association between Pandemrix and narcolepsy showed, the vaccine manufacturer, GlaxoSmithKline funded research to investigate what, if any, in the vaccine could trigger the disease. narcolepsy researcher Emmanuel Mignot of Stanford University, which received grants, already suspected that the rogue immune cells could contribute to narcolepsy. in 09, Mignot and his colleagues found that almost all patients with narcolepsy have a particular human leukocyte antigen (HLA) type. HLA proteins present-pieces antigens abroad T cells, which then coordinate the immune attack. The method allows the immune system to distinguish between self and foreign cells and certain HLA types are associated with autoimmune diseases such as type 1 diabetes and multiple sclerosis. But there is no obvious sign of immune attack in the narcoleptic brain.
In the new work, Mignot, Stanford immunologist Elizabeth Mellins, and his colleagues have developed an immune system cell line that carries the HLA associated with narcolepsy. They combined the cell line with short pieces of protein hypocretin, is then added T cells of patients and controls in combination.
The team had access to four pairs of identical twins in which one twin had narcolepsy but the other did not. In each case, the cells of the affected double T-reacted strongly with hypocretin "epitopes" displayed by HLA-bearing cells, but the cells of the healthy twin T does not. The researchers found the same pattern when they compared cells from 10 Irish children who developed narcolepsy after receiving the Pandemrix vaccine with T cells of siblings healthy patients, who all had the same HLA type and were also vaccinated T. The T cells of patients responded to hypocretin epitope, while their siblings cells not.
They then asked if the H1N1 virus itself could provoke the same immune response. A search on the power to certain sections of a key component of the H1N1 virus, the hemagglutinin protein, which "amazingly air had the same" as the hypocretin epitopes, Mignot said. Indeed, in laboratory tests the viral protein fragment activated hypocretin-reactive immune cells that evidence high narcolepsy may be due to a process known as molecular mimicry, wherein protein fragments from an invading virus or other first pathogen immune system to respond native proteins with similar molecular structure.
results are "exactly what we expected," says Hanna Nohynek vaccine expert at the National Institute for Health and Welfare in Helsinki, which was part of the team that first identified the increased risk of narcolepsy in children who received Pandemrix.
But molecular mimicry alone can not explain the mystery. It is unclear how an immune response to hypocretin could lead to the destruction of neurons that produce, such as reactive cells in the blood would not necessarily meet those brain cells.
And it is still unclear whether the single H1N1 could trigger narcolepsy. Mignot and colleagues reported an increase in the disease in unvaccinated Chinese children who had the virus. But researchers in South Korea and Europe have found no increased risk of the disease in people who have had swine flu.
"There is a lot of work to do," said Steven Black vaccine expert medical Children's Hospital of Cincinnati in Ohio, who is studying possible links between vaccines against H1N1 and narcolepsy. But the work "is the first mechanistic explanation of the disease," which should help researchers home Pandemrix factor that could have caused problems. Identify what, he said, "is a first step" to be able to produce even safer vaccines.
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